1. Field of the Invention
The invention is related to apparatus and methods for determining characteristics of a target tissue of a patient.
2. Background of the Related Art
It is known to irradiate a target tissue with electromagnetic radiation and to detect returned electromagnetic radiation to determine characteristics of the target tissue. In known, methods, the amplitudes and wavelengths of the returned radiation are analyzed to determine characteristics of the target tissue. For instance, U.S. Pat. No. 4,718,417 to Kittrell et al. discloses a method for, diagnosing the type of tissue within an artery, wherein a catheter is inserted into an artery and excitation light at particular wavelengths is used to illuminate the interior wall of the artery. Material or tissue within the artery wall emits fluorescent radiation in response to the excitation light. A detector detects the fluorescent radiation and analyzes the amplitudes and wavelengths of the emitted fluorescent radiation to determine whether the illuminated portion of the artery wall is normal, or covered with plaque. The contents of U.S. Pat. No. 4,718,417 are hereby incorporated by reference.
U.S. Pat. No. 4,930,516 to Alfano et al. discloses a method for detecting cancerous tissue, wherein a tissue sample is illuminated with excitation light at a first wavelength, and fluorescent radiation emitted in response to the excitation light is detected. The wavelength and amplitude of the emitted fluorescent radiation are then examined to determine whether the tissue sample is cancerous or normal. Normal tissue will typically have amplitude peaks at certain known wavelengths, whereas cancerous tissue will have amplitude peaks at different wavelengths. Alternatively, the spectral amplitude of normal tissue will differ from cancerous tissue at the same wavelength. The disclosure of U.S. Pat. No. 4,930,516 is hereby incorporated by reference.
Still other patents, such as U.S. Pat. No. 5,369,496 to Alfano et al., disclose methods for determining characteristics of biological materials, wherein a target tissue is illuminated with light, and backscattered or reflected light is analyzed to determine the tissue characteristics. The contents of U.S. Pat. No. 5,369,496 are hereby incorporated by reference.
These methods rely on the information from steady state emissions to perform a diagnostic measurement. It is known that the accuracy of measurements made by these methods is limited by practical issues such as variation in lamp intensity and changes in fluorophore concentration. It is desirable to measure an intrinsic physical property to eliminate errors that can be caused by practical problems, to thereby make an absolute measurement with greater accuracy. One intrinsic physical property is the fluorescence lifetime or decay time of fluorophores being interrogated, the same fluorophores that serve as indicators of disease in tissue.
It is known to look at the decay time of fluorescent emissions to determine the type or condition of an illuminated tissue.
To date, apparatus for detection of the lifetime of fluorescent emissions have concentrated on directly measuring the lifetime of the fluorescent emissions. Typically, a very short burst of excitation light is directed at a target tissue, and fluorescent emissions from the target tissue are then sensed with a detector. The amplitude of the fluorescent emissions are recorded, over time, as the fluorescent emissions decay. The fluorescent emissions may be sensed at specific wavelengths, or over a range of wavelengths. The amplitude decay profile, as a function of time, is then examined to determine a property or condition of the target tissue. For instance, U.S. Pat. No. 5,562,100 to Kittrell et al. discloses a method of determining tissue characteristics that includes illuminating a target tissue with a short pulse of excitation radiation at a particular wavelength, and detecting fluorescent radiation emitted by the target tissue in response to the excitation radiation. In this method, the amplitude of the emitted radiation is recorded, over time, as the emission decays. The amplitude profile is then used to determine characteristics of the target tissue. Similarly, U.S. Pat. No. 5,467,767 to Alfano et al. also discloses a method of determining whether a tissue sample includes cancerous cells, wherein the amplitude decay profile of fluorescent emissions are examined. The contents of U.S. Pat. Nos. 5,562,100 and 5,467,767 are hereby incorporated by reference.
Unfortunately, these methods require expensive components that are capable of generating extremely short bursts of excitation light, and that are capable of recording the relatively faint fluorescent emissions that occur over time. The high cost of these components has prevented these techniques from being used in typical clinical settings. Other U.S. patents have explained that the decay time of fluorescent emissions can be indirectly measured utilizing phase shift or polar anisotropy measurements. For instance, U.S. Pat. No. 5,624,847 to Lakowicz et al. discloses a method for determining the presence or concentration of various substances using a phase shift method. U.S. Pat. No. 5,515,864 to Zuckerman discloses a method for measuring the concentration of oxygen in blood utilizing a polar anisotropy measurement technique. Each of these methods indirectly measure the lifetime of fluorescent emissions generated in response to excitation radiation. The contents of U.S. Pat. Nos. 5,624,847 and 5,515,864 are hereby incorporated by reference.
The invention encompasses apparatus and methods for determining characteristics of target tissues within or at the surface of a patient""s body, wherein excitation electromagnetic radiation is used to illuminate a target tissue and electromagnetic radiation returned from the target tissue is analyzed to determine the characteristics of the target tissue. Some apparatus and methods embodying the invention can be used to perform a diagnosis at or slightly below the surface of a patient""s tissues. For instance, methods and apparatus embodying the invention could be used to diagnose the condition of a patient""s skin, the lining of natural body lumens such as the gastrointestinal tract, or the surfaces of body organs or blood vessels. Embodiments of the invention are particularly well suited to analyzing epithelial tissue. Other apparatus and methods embodying the invention can be used to perform a diagnosis deep within a patient""s body tissues where the excitation radiation has to pass through several centimeters of tissue before it interacts with the target tissue, such as in diagnosis of tumors and lesions deep in a patient""s breast.
The returned electromagnetic radiation can comprise electromagnetic radiation that is scattered or reflected from or transmitted through the target tissue. Analysis of the scattered, reflected or transmitted excitation radiation gives a measure of absorption and scattering characteristics of the target tissue. This information can be used by itself to provide a diagnosis, or the information can be used in conjunction with the results of fluorescent emission measurements, as discussed below, to arrive at a more accurate measurement. The reflected or scattered excitation radiation can be measured using intensity based techniques, phase shift techniques, or polarization anisotropy based techniques. While polarization preserving fiber optics are not currently available, should they be developed in the future, polar anisotropic techniques could also be used.
The returned electromagnetic radiation can also comprise only fluorescent emissions from the target tissue that are caused by the excitation electromagnetic radiation. In this instance, apparatus or methods embodying the invention would measure the lifetime or decay time of the fluorescent emissions and use this information to determine characteristics of the target tissue. The fluorescent emissions may be generated by endogenous or exogenous fluorescent materials in the target tissue. Both phase shift and polar anisotropy techniques could be used to perform these types of measurements.
A device or method embodying the invention can be used to determine the conditions of multiple portions of a target tissue, and the determined conditions can be used to create a map of the target tissue. Such a map could then be either displayed on a display screen, or presented in hard copy format.
An instrument embodying present invention could be in the form of an endoscope designed to be introduced into a natural lumen or a cavity of a patient""s body. Alternatively, the instrument might be in the form of a catheter designed to be introduced into blood vessels of a patient""s body. Regardless of whether the apparatus is in the form of an endoscope or a catheter, the apparatus could include means for delivering a therapeutic pulse of electromagnetic radiation to the target tissue. The device could also include means for delivering a therapeutic dose of medication to the target tissue. Further, the instrument could include means for sampling the target tissue depending upon the determined condition of the target tissue.
An apparatus embodying the invention that is well suited to developing a map of target tissue conditions may include a plurality of optical fibers that are arranged in a predetermined pattern on the face of a test instrument. Each optical fiber would be capable of delivering excitation radiation and conducting return radiation to a detector. Alternatively, each detection position on the face of the instrument could include at least one optical fiber for delivering excitation radiation and at least one separate fiber for receiving returned radiation. In yet other alternatives, multiple fibers could be used at each position for the excitation or return radiation, or both. By pressing the face of the instrument against the target tissue, multiple measurements can be taken at multiple positions simultaneously.
An apparatus as described above could also be configured so that once a first set of measurements are taken with the instrument, the locations of the optical fibers could be moved incrementally, and a second set of measurements could be recorded. This could be done by repositioning the instrument face, or by keeping the instrument face stationary, and repositioning the optical fibers behind the instrument face. This process could be repeated several times to obtain multiple sets of readings from the target tissue. The additional sets of measurements could be taken on the same area as the first set, or at different locations on the target tissue.
An instrument as described above could be configured to allow rotation of the optical fibers between a plurality of predetermined rotational positions. One embodiment could be configured so that the optical fibers are located at a series of unique positions as the optical fibers are rotated between the predetermined rotational positions. This would allow the device to capture multiple readings at a large number of unique positions on the target tissue. Such a multiple cycle measurement process would allow the optical fibers to be spaced far enough apart to reduce or eliminate cross-talk, while still providing greater resolution than would be possible with a single measurement cycle.
An instrument for determining characteristics of a target material according to the invention could include a probe face configured to conform to a non-uniform and/or non-planar surface area of a target material. According to one embodiment, the probe face could be shaped to conform to a non-uniform surface area of a target material. For example, the probe body could be a fused glass cane, where one end of the fused cane is shaped to conform to a non-uniform surface area of a target material. Further, the probe body could be attached to a flexible bundle of optic fibers. The instrument could comprise an outer housing, an inner core and a probe face attached to the inner core and comprising a plurality of interrogation devices arranged in a predetermined pattern.
According to another embodiment, of the invention, the instrument could include an inner core that is rotatably mounted within the housing, where the probe face is mounted on the inner core. The inner core could comprise a first inner core and a second inner core. The second inner core would preferably be configured to slide axially inside the first inner core and rotate with the first inner core when the first inner core is rotated. The probe face would preferably comprise first and second probe faces. The first probe face would preferably be attached to the first inner core and have a centrally located opening for allowing the second inner core to axially slide with respect to the first inner core such that the second probe face is not located in the same plane as the first probe face.
According to another embodiment of the invention, a plurality of interrogation devices may be spring-loaded in the probe face so that the plurality of interrogation devices collectively conform to a non-uniform surface area of a target material. Preferably, each of the plurality of interrogation devices comprises a hollow shaft within which the respective interrogation device is axially movably disposed, the hollow shaft being positioned in the probe face. A spring disposed within the hollow shaft would allow the interrogation device to move axially within the hollow shaft to allow the interrogation devices to collectively conform to a non-uniform surface area of a target material. The plurality of interrogation devices may comprise a plurality of optical fibers.
In some embodiments, the device could include a detector array, such as a CCD. Light scattered from or generated by a target material could be conducted to the detector array by at least some of the optical fibers.
Any of the above discussed instruments may include a flexible sheath configured to cover and conform to the shape of the probe face. The flexible sheath is preferably optically clear, optically uniform, disposable, and formed of a material having a low durometer and high tear strength. Further, an index matching agent may be located between the flexible sheath and the plurality of interrogation devices.
A method of detecting characteristics of a target material according to the invention preferably comprises positioning a plurality of interrogation devices that are arranged in a pattern adjacent a first plurality of interrogation positions on a non-uniform surface area of a target material so that the plurality of interrogation devices conform to the non-uniform surface area, and detecting characteristics of the target material at the first plurality of interrogation positions.
The method may further comprise repositioning the plurality of interrogation devices so that they are adjacent at least one additional plurality of interrogation positions on the target material, and detecting characteristics of the target material at the at least one additional plurality of interrogation positions. Preferably, the first and at least one additional plurality of positions are not coincident. The repositioning step may comprise rotating the plurality of interrogation devices around a common axis. The method could further include steps of withdrawing the probe from the target material before conducting the rotation step, and then advancing the probe back into contact with the target material after the rotation has been accomplished.
Each detecting step may comprise detecting a first type of characteristics of the target material at a plurality of interrogation positions, and detecting a second type of characteristics of the target material at the same plurality of interrogation positions. The first type of characteristics may comprise scattering characteristics, and the second type of characteristics may comprise fluorescent characteristics.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objects and advantages of the invention may be realized and attained as particularly pointed out in the appended claims.